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Relationship: 868

Title

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Induction, CYP1A2/CYP1A5 leads to Oxidation, Uroporphyrinogen

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Aryl hydrocarbon receptor activation leading to uroporphyria adjacent Moderate Low Amani Farhat (send email) Open for citation & comment WPHA/WNT Endorsed

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI
human Homo sapiens High NCBI
chicken Gallus gallus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

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Term Evidence
Adults High
Juvenile High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

The oxidation of uroporphyrinogen to its corresponding porphyrin (UROX) is preferentially catalyzed by the phase one metabolizing enzyme, CYP1A2, in mammals[1][2] and CYP1A5 in birds[3]. Uroporphyrinogen, an intermediate in heme biosynthesis, is normally converted to coproporphyrinogen by uroporphyrinogen decarboxylase (UROD)[4]; induction of CYP1A2 expression translates to increased protein levels and therefore an increased incidence of binding, and oxidation of uroporphyrinogen, preventing its normally dominant conversion to coproporphyrinogen.

Evidence Collection Strategy

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Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

WOE for this KER is moderate.

Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Uroporphyrinogen has clearly been identified as a substrate of CYP1A2/5, which results in its oxidation to uroporphyrin[1][2][3].

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

It is worth noting that Cyp1a2(-/-) knockout mice have up to 40% of the UROX activity of Cyp1a2(+/+) mice[7], suggesting that some UROX activity is CYP1A2-independent. Likewise, transfection of human Cyp1a1, Cyp3a4, Cyp3a5, or Cyp2e1 in insect cells resulted in UROX activity[10], suggesting that UROX can be catalyzed by other CYPs than CYP1A2 both in mouse and human. Additionally, iron overload or other induced pathways can potentially induce UROX [13]. However, it was shown in mice that only CYP1A2-dependent UROX activity is associated with UROD inhibition[7]. No such experiment was conducted in human, therefore, uncertainties remain for that species. 

In mice, TCDD can elicit AhR-dependent, CYP1A1/A2-independent mitochondrial ROS production suggesting that general oxidative stress induced independently of CYP1A2 induction may contribute to the resulting overall UROX by TCDD [14].  

Phillips et al.[11] were able to generate uroporphyria in a Cyp1A2-/- mouse model that is genetically predisposed (Hfe-/-, Urod-/+, which translates into intrinsic iron-overload and reduced UROD activity) to develop porphyria in the absence of external stimuli; CYP1A2 knockout alone prevented porphyrin accumulation, but with the addition of iron and ALA to the triple knockout, modest porphyria was observed. Therefore, under extreme porphyric conditions, UROX leading to porphyria can occur in the absence of the CYP1A2 enzyme.

Altogether, these results indicate that while CYP1A2 is a major catalysis of UROX activity, other CYPs and/or modulating factors are involved in the pathway.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

Iron

Iron status can profoundly modify the level of uroporphyrin accumulation especially in mice. In fact iron overload alone of mice will eventually produce a strong hepatic uroporphyria which is markedly genetically determined and toxicity can be ameliorated by chelators [15-16]. In human suffering from uroporphyrin accumulation, it was found that lowering body iron stores by bleeding or now chelators causes remission [17].

Cycling between the ferrous (Fe2+) and ferric (Fe3+) redox states allows Fe to catalyze the Haber-Weiss reaction, in which highly reactive OH is generated from H2O2 and O2•−. Thus, by catalyzing the formation of reactive oxygen species, it is suggested that iron can increase the rate at which uroporphyrinogen is oxidized to uroporphyrin and therefore enhance uroporphyrin formation [18].

Ascorbic acid

Ascorbic acid (AA) can prevent uroporphyrin accumulation experimental uroporphyria, but only when hepatic iron stores are normal or mildly elevated [19]. It was shown in chick embryo liver cells that AA could prevent uroporphyrin accumulation caused by treatment with 3,3',4,4'-tetrachlorobiphenyl and 5-aminole-vulinate by competitively inhibiting microsomal CYP1A2-catalyzed oxidation of uroporphyrinogen[20]. Oppositely, in a spontaneous mutant rat that requires dietary AA, hepatic uroporphyrin accumulation caused by treatment with 3-methylcholanthrene or hexachlorobenzene was found to be enhanced when the animals were maintained on a very low AA dietary intake[21].

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

CYP1A2 catalyzes UROX in mice, rats and humans[1][2][11], as does CYP1A5 in chickens[3] .

References

List of the literature that was cited for this KER description. More help
  1. 1.0 1.1 1.2 1.3 Jacobs, J. M., Sinclair, P. R., Bement, W. J., Lambrecht, R. W., Sinclair, J. F., and Goldstein, J. A. (1989). Oxidation of uroporphyrinogen by methylcholanthrene-induced cytochrome P-450. Essential role of cytochrome P-450d. Biochem. J 258 (1), 247-253.
  2. 2.0 2.1 2.2 2.3 Lambrecht, R. W., Sinclair, P. R., Gorman, N., and Sinclair, J. F. (1992). Uroporphyrinogen oxidation catalyzed by reconstituted cytochrome P450IA2. Arch. Biochem. Biophys. 294 (2), 504-510.
  3. 3.0 3.1 3.2 Sinclair, P. R., Gorman, N., Walton, H. S., Sinclair, J. F., Lee, C. A., and Rifkind, A. B. (1997). Identification of CYP1A5 as the CYP1A enzyme mainly responsible for uroporphyrinogen oxidation induced by AH receptor ligands in chicken liver and kidney. Drug Metab. Dispos. 25 (7), 779-783.
  4. 4.0 4.1 Elder, G. H., and Roberts, A. G. (1995). Uroporphyrinogen decarboxylase. J Bioenerg. Biomembr. 27 (2), 207-214.
  5. 5.0 5.1 Gorman, N., Ross, K. L., Walton, H. S., Bement, W. J., Szakacs, J. G., Gerhard, G. S., Dalton, T. P., Nebert, D. W., Eisenstein, R. S., Sinclair, J. F., and Sinclair, P. R. (2002). Uroporphyria in mice: thresholds for hepatic CYP1A2 and iron. Hepatology 35 (4), 912-921.
  6. Greaves, P., Clothier, B., Davies, R., Higginson, F. M., Edwards, R. E., Dalton, T. P., Nebert, D. W., and Smith, A. G. (2005) Uroporphyria and hepatic carcinogenesis induced by polychlorinated biphenyls-iron interaction: absence in the Cyp1a2(-/-) knockout mouse. Biochem. Biophys. Res. Commun. 331 (1), 147-152.
  7. Sinclair, P. R., Gorman, N., Dalton, T., Walton, H. S., Bement, W. J., Sinclair, J. F., Smith, A. G., and Nebert, D. W. (1998) Uroporphyria produced in mice by iron and 5-aminolaevulinic acid does not occur in Cyp1a2(-/-) null mutant mice. Biochem. J. 330 ( Pt 1), 149-153.
  8. Smith, A. G., Clothier, B., Carthew, P., Childs, N. L., Sinclair, P. R., Nebert, D. W., and Dalton, T. P. (2001) Protection of the Cyp1a2(-/-) null mouse against uroporphyria and hepatic injury following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Appl. Pharmacol. 173 (2), 89-98.
  9. Davies, R., Clothier, B., Robinson, S. W., Edwards, R. E., Greaves, P., Luo, J., Gant, T. W., Chernova, T., and Smith, A. G. (2008) Essential role of the AH receptor in the dysfunction of heme metabolism induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Chem. Res. Toxicol. 21 (2), 330-340.
  10. Sinclair, P. R., Gorman, N., Tsyrlov, I. B., Fuhr, U., Walton, H. S., and Sinclair, J. F. (1998b). Uroporphyrinogen oxidation catalyzed by human cytochromes P450. Drug Metab Dispos. 26 (10), 1019-1025.
  11. 11.0 11.1 11.2 Phillips, J. D., Kushner, J. P., Bergonia, H. A., and Franklin, M. R. (2011) Uroporphyria in the Cyp1a2-/- mouse. Blood Cells Mol. Dis. 47 (4), 249-254.
  12. van Birgelen, A. P., DeVito, M. J., Akins, J. M., Ross, D. G., Diliberto, J. J., and Birnbaum, L. S. (1996). Relative potencies of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls derived from hepatic porphyrin accumulation in mice. Toxicol. Appl. Pharmacol. 138 (1), 98-109.
  13. Caballes F.R., Sendi, H., and Bonkovsky, H. L. (2012). Hepatitis C, porphyria cutanea tarda and liver iron: an update. Liver Int. 32 (6), 880-893.
  14. Senft, A.P., Dalton, T.P., Nebert, D.W., Genter, M.B., Puga, A., Hutchinson, R.J., Kerzee, J.K., Uno, S., and Shertzer, H.G. (2002). Mitochondrial reactive oxygen production is dependent on the aromatic hydrocarbon receptor. Free Radic Biol Med 33, 1268-1278.

  15. Smith, A. G., & Francis, J. E. (1993). Genetic variation of iron-induced uroporphyria in mice. Biochemical Journal291 (1), 29.
  16. Gorman, N., Zaharia, A., Trask, H. S., Szakacs, J. G., Jacobs, N. J., Jacobs, J. M., Sinclair, P. R. (2007). Effect of an oral iron chelator or iron‐deficient diets on uroporphyria in a murine model of porphyria cutanea tarda. Hepatology46 (6), 1927-1834.
  17. Ippen H. (1977). Treatment of porphyria cutanea tarda by phlebotomy. Semin Hematol.14, 253-9.
  18. Fader, K. A., Nault, R., Kirby, M. P., Markous, G., Matthews, J., & Zacharewski, T. R. (2017). Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity. Toxicology and applied pharmacology321, 1-17.
  19. Gorman, N., Zaharia, A., Trask, H. S., Szakacs, J. G., Jacobs, N. J., Jacobs, J. M., ... & Sinclair, P. R. (2007). Effect of iron and ascorbate on uroporphyria in ascorbate‐requiring mice as a model for porphyria cutanea tarda. Hepatology, 45 (1), 187-194.
  20. Sinclair PR, Gorman N, Walton HS, Bement WJ, Jacobs JM, Sinclair JF. (1993). Ascorbic acid inhibition of cytochrome P450-catalyzed uroporphyrin accumulation. Arch Biochem Biophys. 304, 464-470.
  21. Sinclair PR, Gorman N, Sinclair JF, Walton HS, Bement WJ, Lambrecht RW. (1995). Ascorbic acid inhibits chemically induced uroporphyria in ascorbate-requiring rats. Hepatology. 22, 565-572.